A new mechanisms of G-CSF effect against myocardial infarction - molecular mechanism of healing process acceleration -

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The purpose of the present study was to define whether the improvement of cardiac function and remodeling after infarction (MI) by G-CSF relates to acceleration of the healing process from absorption of necrotic tissues into granulation and then scarring, in addition to myocardial regeneration. In a 30-minute coronary occlusion and reperfusion rabbit model, saline (S) or 10 μg/kg/day of human recombinant G-CSF (G) was subcutaneously injected from 1 to 5 days after MI. Smaller left ventricular (LV) dimension, increased LV ejection fraction and thicker infarct-LV wall were seen in G at 3 months after MI. At 2 days, 7 days, 14 days and 3 months after MI, necrotic tissue areas were 14.2±1.5/13.4±1.1, 0.4±0.1/1.8±0.5^*, 0/0 and 0/0 mm^2/slice/kg, granulation areas 0/0, 4.0±0.7/8.5±1.0^*, 3.9±0.8/5.7±0.7^* and 0/0 mm^2/slice/kg, scar areas 0/0, 0/0, 0/0 and 4.2±0.5/7.9±0.9^* mm^2/slice/kg in G and S, respectively (^* : p<0.05,G vs S). Clear increases of macrophages with positive RAM 11 and of matrix metalloproteinase (MW) 1 and 9 were seen in G at 7 days after MI. This suggests that G accelerates absorption of necrotic tissues via increase of macrophages and reduces granulation and scar tissues via expression of MMPs. Meanwhile, survived myocardial tissue areas within the risk areas were significantly increased in G despite no significant difference in LV weight, LV wall area and size of cardiomyocytes between G and S. Confocal microscopy revealed significant increases of cardiomyocytes with positive DiI (a marker of bone marrow cells) and positive troponin I (a marker of cardiomyocytes) or CD-31 (a marker of endothelial cells) in G, suggesting enhanced myocardial regeneration by G. In conclusion, the acceleration of the healing process as well as myocardial regeneration may play an important role for the beneficial effect of post-MI G-CSF treatment.